Bicyclic heterocylces, pharmaceutical compositions containing these compounds, their use and processes for preparing them

ABSTRACT

The present invention relates to bicyclic heterocycles of general formula  
                 
wherein 
 
R a , R b , R c , R d , R e  and X are defined as in claim  1 , the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids, which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases and benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract, and the preparation thereof.

The present invention relates to bicyclic heterocycles of generalformula

the tautomers, the stereoisomers, the mixtures thereof and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids, which have valuable pharmacologicalproperties, particularly an inhibitory effect on signal transductionmediated by tyrosine kinases, the use thereof for treating diseases,particularly tumoral diseases and benign prostatic hyperplasia (BPH),diseases of the lungs and respiratory tract, and the preparationthereof.

In the above general formula I

R^(a) denotes a hydrogen atom or a C₁₋₄-alkyl group,

R^(b) denotes a phenyl, benzyl or 1-phenylethyl group, wherein thephenyl nucleus in each case is substituted by the groups R¹ to R³, while

-   -   R¹ and R², which may be identical or different, in each case        denote a hydrogen, fluorine, chlorine, bromine or iodine atom,    -   a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, C₂₋₃-alkenyl or C₂₋₃-alkynyl        group,    -   an aryl, aryloxy, arylmethyl or arylmethoxy group,    -   a heteroaryl, heteroaryloxy, heteroarylmethyl or        heteroarylmethoxy group,    -   a methyl or methoxy group substituted by 1 to 3 fluorine atoms        or    -   a cyano, nitro or amino group, and    -   R³ denotes a hydrogen, fluorine, chlorine or bromine atom,    -   a methyl or trifluoromethyl group,

R^(c) denotes a hydrogen atom or a fluorine, chlorine or bromine atom,

a hydroxy or C₁₋₄-alkyloxy group,

a methoxy group substituted by 1 to 3 fluorine atoms,

an ethyloxy group substituted by 1 to 5 fluorine atoms,

a C₂₋₄-alkyloxy group which is substituted by a group R⁴, while

-   -   R⁴ denotes a hydroxy, C₁₋₃-alkyloxy, C₃₋₆-cycloalkyloxy,        C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)amino, bis-(2-C₁₋₃-alkyloxy-ethyl)-amino,        bis-(3-C₁₋₃-alkyloxy-propyl)-amino, pyrrolidin-1-yl,        piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl,        homomorpholin-4-yl, piperazin-1-yl,        4-(C₁₋₃-alkyl)-piperazin-1-yl, homopiperazin-1-yl or        4-(C₁₋₃-alkyl)-homopiperazin-1-yl group,

a C₃₋₇-cycloalkyloxy or C₃₋₇-cycloalkyl-C₁₋₄-alkyloxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy ortetrahydropyran-4-yloxy group,

a tetrahydrofuranyl-C₁₋₄-alkyloxy or tetrahydropyranyl-C₁₋₄-alkyloxygroup,

a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy group,

a 1-(C₁₋₃-alkyl)-pyrrolidin-3-yloxy, 1-(C₁₋₃-alkyl)-piperidin-3-yloxy or1-(C₁₋₃-alkyl)-piperidin-4-yloxy group,

a C₁₋₄-alkoxy group which is substituted by a pyrrolidinyl, piperidinylor homopiperidinyl group substituted in the 1 position by the group R⁵,where

-   -   R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,

or a C₁₋₄-alkoxy group which is substituted by a morpholinyl orhomomorpholinyl group substituted in the 4 position by the group R⁵,where R⁵ is as hereinbefore defined,

R^(e) and R^(d), which may be identical or different, in each casedenote a hydrogen atom or a C₁₋₃-alkyl group and

X denotes a methyne group substituted by a cyano group or a nitrogenatom,

while by the aryl groups mentioned in the definition of the above groupsis meant in each case a phenyl group which is mono- or disubstituted byR⁶, while the substituents may be identical or different and

-   -   R⁶ denotes a hydrogen atom, a fluorine, chlorine, bromine or        iodine atom or a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy,        difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy or cyano group,

by the heteroaryl groups mentioned in the definition of the above groupsis meant a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, whilethe above-mentioned heteroaryl groups are mono- or disubstituted in eachcase by the group R⁶, while the substituents may be identical ordifferent and R⁶ is as hereinbefore defined, and

unless otherwise stated, the above-mentioned alkyl groups may bestraight-chain or branched.

Preferred compounds of the above general formula I are those wherein

R^(a) denotes a hydrogen atom,

R^(b) denotes a phenyl group substituted by the groups R¹ to R³, while

-   -   R¹ denotes a hydrogen, fluorine, chlorine or bromine atom,    -   a methyl, trifluoromethyl or ethynyl group,    -   a phenyloxy or phenylmethoxy group, while the phenyl moiety of        the above-mentioned groups is optionally substituted by a        fluorine or chlorine atom, or    -   a pyridinyloxy or pyridinylmethoxy group, while the pyridinyl        moiety of the above-mentioned groups is optionally substituted        by a methyl or trifluoromethyl group,    -   R² denotes a hydrogen, fluorine or chlorine atom and    -   R³ denotes a hydrogen atom,

R^(c) denotes a hydrogen atom,

a C₁₋₃-alkyloxy group,

a C₄₋₆-cycloalkyloxy or C₃₋₆-cycloalkyl-C₁₋₂-alkyloxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₂-alkyloxy ortetrahydropyranyl-C₁₋₂-alkyloxy group,

an ethyloxy group which is substituted in the 2 position by a group R⁴,where

-   -   R⁴ denotes a hydroxy, C₁₋₃-alkyloxy, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)amino, bis-(2-methoxyethyl)-amino,        pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl,        morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl,        4-(C₁₋₃-alkyl)-piperazin-1-yl, homopiperazin-1-yl or        4-(C₁₋₃-alkyl)-homopiperazin-1-yl group,

a propyloxy group which is substituted by a group R⁴ in the 3 position,while R⁴ is as hereinbefore defined, or

a butyloxy group which is substituted by a group R⁴ in the 4 position,while R⁴ is as hereinbefore defined,

R^(e) and R^(d), which may be identical or different, in each casedenote a hydrogen atom or a methyl group and

X denotes a nitrogen atom,

while, unless otherwise stated, the above-mentioned alkyl groups may bestraight-chain or branched,

the tautomers, their stereoisomers, the mixtures thereof and the saltsthereof.

Particularly preferred compounds of the above general formula I arethose wherein

R^(a) denotes a hydrogen atom,

R^(b) denotes a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or3-chloro-4-fluoro-phenyl group,

R^(c) denotes a hydrogen atom,

a methoxy, ethyloxy, 2-(methoxy)ethyloxy, 3-(morpholin-4-yl)propyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy,cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, tetrahydrofuran-2-yl methoxy,tetrahydrofuran-3-yl methoxy or tetrahydropyran-4-ylmethoxy group,

R^(e) and R^(d) in each case denote a hydrogen atom and

X denotes a nitrogen atom,

the tautomers, their stereoisomers, the mixtures thereof and the saltsthereof.

Most particularly preferred compounds of general formula I are thosewherein

R^(a) denotes a hydrogen atom,

R^(b) denotes a 3-chloro-4-fluoro-phenyl group,

R^(c) denotes a tetrahydrofuran-3-yloxy group,

R^(e) and R^(d) in each case denote a hydrogen atom and

X denotes a nitrogen atom,

the tautomers, their stereoisomers, the mixtures thereof and the saltsthereof.

The following particularly preferred compound of general formula I ismentioned by way of example:

-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline

and the salts thereof.

The compounds of general formula I may be prepared by the followingmethods, for example:

a) reacting a compound of general formula

wherein

R^(a), R^(b), R^(c) and X are as hereinbefore defined and R⁷ and R⁸,which may be identical or different, denote C₁₋₄-alkyl groups, with acompound of general formula

wherein

R^(d) and R^(e) are as hereinbefore defined.

The reaction is expediently carried out in a solvent or mixture ofsolvents such as tetrahydrofuran, tetrahydrofuran/water, acetonitrile,acetonitrile/water, dioxane, ethyleneglycol dimethyl ether, isopropanol,methylene chloride, dimethylformamide or sulpholane, optionally in thepresence of an inorganic or organic base, e.g. sodium carbonate,potassium hydroxide or 1,8-diazabicyclo[5.4.0]undec-7-ene and optionallyin the presence of a lithium salt such as lithium chloride attemperatures between −50 and 150° C., but preferably at temperaturesbetween −20 and 80° C. The reaction may also be carried out with areactive derivative of the compound of general formula III, for examplethe hydrate or a hemiacetal.

b) reacting a compound of general formula

wherein

R^(a), R^(b), R^(c) and X are as hereinbefore defined and Z¹ denotes aleaving group such as a halogen atom or a substituted sulphonyloxy groupsuch as a chlorine or bromine atom, a methanesulphonyloxy orp-toluenesulphonyloxy group, with a compound of general formula

wherein R^(d) and R^(e) are as hereinbefore defined.

The reaction is expediently carried out in a solvent such asisopropanol, butanol, tetrahydrofuran, dioxane, acetonitrile,dimethylformamide, sulpholane, toluene or methylene chloride or mixturesthereof, optionally in the presence of an inorganic or organic base,e.g. sodium carbonate, potassium carbonate, potassium hydroxide,triethylamine or N-ethyl-diisopropylamine and optionally in the presenceof a reaction accelerator such as an alkali metal iodide at temperaturesbetween −20 and 150° C., but preferably at temperatures between 0 and100° C. The reaction may however also be carried out without a solventor in an excess of the compound of general formula V used.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, amino, alkylamino or imino groups may be protectedduring the reaction by conventional protecting groups which are cleavedagain after the reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group may be aformyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at temperatures between 20 and 60°C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane, optionally using a solvent suchas methylene chloride, dioxane, methanol or diethylether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid at temperatures between 50 and 120° C. or by treatingwith sodium hydroxide solution optionally in the presence of a solventsuch as tetrahydrofuran at temperatures between 0 and 50° C.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-O-p-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a(+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid or maleic acid.

As already mentioned hereinbefore, the compounds of general formula Iaccording to the invention and the physiologically acceptable saltsthereof have valuable pharmacological properties, particularly aninhibiting effect on signal transduction mediated by the EpidermalGrowth Factor receptor (EGF-R), whilst this may be achieved for exampleby inhibiting ligand bonding, receptor dimerisation or tyrosinekinaseitself. It is also possible to block the transmission of signals tocomponents located further downstream.

The biological properties of the new compounds were investigated asfollows:

The inhibition of human EGF-receptor kinase was determined using thecytoplasmatic tyrosine kinase domain (methionine 664 to alanine 1186,based on the sequence published in Nature 309 (1984), 418). To do this,the protein was expressed in Sf9 insect cells as a GST fusion proteinusing the Baculovirus expression system.

The enzyme activity was measured in the presence or absence of the testcompounds in serial dilutions. The polymer pEY (4:1) produced by SIGMAwas used as the substrate. Biotinylated pEY (bio-pEY) was added as thetracer substrate. Every 100 μl of reaction solution contained 10 μl ofthe inhibitor in 50% DMSO, 20 μl of the substrate solution (200 mM HEPESpH 7.4, 50 mM magnesium acetate, 2.5 mg/ml of poly(EY), 5 μg/ml ofbio-pEY) and 20 μl of enzyme preparation. The enzyme reaction wasstarted by the addition of 50 μl of a 100 μM ATP solution in 10 mMmagnesium chloride. The dilution of the enzyme preparation was adjustedso that the incorporation of phosphate into the bio-pEY was linear interms of time and quantity of enzyme. The enzyme preparation was dilutedin 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% TritonX-100, 1 mM DTT and 10% glycerol.

The enzyme assays were carried out at ambient temperature over a periodof 30 minutes and were ended by the addition of 50 μl of a stoppingsolution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μl were placed on astreptavidin-coated microtitre plate and incubated for 60 minutes atambient temperature. Then the plate was washed with 200 μl of a washingsolution (50 mM Tris, 0.05% Tween 20). After the addition of 100 μl of aHRPO-labelled anti-PY antibody (PY20H Anti-PTyr:HRP produced byTransduction Laboratories, 250 ng/ml) it was incubated for 60 minutes.Then the microtitre plate was washed three times with 200 μl of washingsolution. The samples were then combined with 100 μl of a TMB-peroxidasesolution (A:B=1:1, Kirkegaard Perry Laboratories). After 10 minutes thereaction was stopped. The extinction was measured at OD_(450 nm) with anELISA reader. All data points were measured three times.

The data were matched using an iterative calculation using an analyticalprogramme for sigmoidal curves (Graph Pad Prism Version 3.0; sigmoidcurves, variable pitch). All the iteration data released showed acorrelation coefficient of more than 0.9. The maxima and minima of thecurves showed a spread of at least a factor of 5. The IC₅₀(concentration of active substance which inhibits the activity ofEGF-receptor kinase by 50%) was determined from the curves.

The following results were obtained: Inhibition of EGF- Compoundreceptor kinase (Example No.) IC₅₀ [nM] 1 1.5

The compounds of general formula I according to the invention thusinhibit signal transduction by tyrosine kinases, as demonstrated by theexample of the human EGF receptor, and are therefore useful for treatingpathophysiological processes caused by hyperfunction of tyrosinekinases. These are e.g. benign or malignant tumours, particularlytumours of epithelial and neuroepithelial origin, metastasisation andthe abnormal proliferation of vascular endothelial cells(neoangiogenesis).

The compounds according to the invention are also useful for preventingand treating diseases of the airways and lungs which are accompanied byincreased or altered production of mucus caused by stimulation bytyrosine kinases, e.g. in inflammatory diseases of the airways such aschronic bronchitis, chronic obstructive bronchitis, asthma,bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cysticfibrosis, α1-antitrypsin deficiency, or coughs, pulmonary emphysema,pulmonary fibrosis and hyperreactive airways.

The compounds are also suitable for treating diseases of thegastrointestinal tract and bile duct and gall bladder which areassociated with disrupted activity of the tyrosine kinases, such as maybe found e.g. in chronic inflammatory changes such as cholecystitis,Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinaltract or such as may occur in diseases of the gastrointestinal tractwhich are associated with increased secretions, such as Ménétrier'sdisease, secreting adenomas and protein loss syndrome.

In addition, the compounds of general formula I and the physiologicallyacceptable salts thereof may be used to treat other diseases caused byabnormal function of tyrosine kinases, such as e.g. epidermalhyperproliferation (psoriasis), benign prostatic hyperplasia (BPH),inflammatory processes, diseases of the immune system,hyperproliferation of haematopoietic cells, treatment of nasal polyps,etc.

By reason of their biological properties the compounds according to theinvention may be used on their own or in conjunction with otherpharmacologically active compounds, for example in tumour therapy, inmonotherapy or in conjunction with other anti-tumour therapeutic agents,for example in combination with topoisomerase inhibitors (e.g.etoposide), mitosis inhibitors (e.g. vinblastine), compounds whichinteract with nucleic acids (e.g. cis-platin, cyclophosphamide,adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors ofmetabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons),antibodies, etc. For treating respiratory tract diseases, thesecompounds may be used on their own or in conjunction with othertherapeutic agents for the airways, such as substances with asecretolytic (e.g. ambroxol, N-acetylcysteine), broncholytic (e.g.tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/oranti-inflammatory activity (e.g. theophylline or glucocorticoids). Fortreating diseases in the region of the gastrointestinal tract, thesecompounds may also be administered on their own or in conjunction withsubstances having an effect on motility or secretion. These combinationsmay be administered either simultaneously or sequentially.

These compounds may be administered either on their own or inconjunction with other active substances by intravenous, subcutaneous,intramuscular, intraperitoneal or intranasal route, by inhalation ortransdermally or orally, whilst aerosol formulations are particularlysuitable for inhalation.

For pharmaceutical use the compounds according to the invention aregenerally used for warm-blooded vertebrates, particularly humans, indoses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. Foradministration they are formulated with one or more conventional inertcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat orsuitable mixtures thereof in conventional galenic preparations such asplain or coated tablets, capsules, powders, suspensions, solutions,sprays or suppositories.

The following Examples are intended to illustrate the present inventionwithout restricting it:

Preparation of the Starting Compounds:

EXAMPLE I4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(diethoxy-phosphoryl)-acetylamino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline

60.07 g of diethoxyphosphorylacetic acid are placed in 750 ml ofN,N-dimethylformamide and at ambient temperature combined with 48.67 gof N,N′-carbonyldiimidazole. After the development of gas has ceased90.00 g of4-[(3-chloro-4-fluoro-phenyl)amino]-6-amino-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazolineare added and the reaction mixture is stirred for about 4-5 hours atambient temperature until the reaction is complete. The reaction mixtureis then heated gently in the water bath and 750 ml of water are addedtwice. The thick suspension is stirred overnight and the next morninganother 350 ml of water are added. The suspension is cooled in the icebath, stirred for one hour and suction filtered. The filter cake iswashed again with 240 ml of N,N-dimethylformamide/water (1:2) and 240 mlof diisopropylether and dried at 40° C. in the circulating air dryer.

Yield: 117.30 g of (88% of theory)

R_(f) value: 0.37 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=553, 555 [M+H]⁺

The following compounds are obtained analogously to Example I:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(diethoxy-phosphoryl)-acetylamino]-7-[(R)-(tetrahydrofuran-3-yl)oxy]-quinazoline

Mass spectrum (ESI⁺): m/z=553, 555 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(diethoxy-phosphoryl)-acetylamino]-7-cyclopropylmethoxy-quinazoline

melting point: 185-187° C.

(3)4-[(3-bromophenyl)amino]-6-[(diethoxy-phosphoryl)-acetylamino]-quinazoline

Mass spectrum (ESI⁻): m/z=491, 493 [M−H]⁻

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(diethoxy-phosphoryl)-acetylamino]-7-cyclopentyloxy-quinazoline

R_(f) value: 0.54 (silica gel, methylene chloride/ethanol=20:1)

EXAMPLE II Homomorpholin-4-yl-acetaldehyde-hydrochloride

Prepared by stirring (2.5 hours) 4-(2,2-dimethoxy-ethyl)-homomorpholinewith semiconcentrated hydrochloric acid at 80° C. The solution obtainedis further reacted directly as in Example 1.

EXAMPLE III 4-(2,2-dimethoxy-ethyl)-homomorpholine

Prepared by stirring (5 hours) homomorpholine-hydrochloride withbromoacetaldehyde-dimethylacetal in the presence of potassium carbonatein N-methylpyrrolidinone at 80° C.

R_(f) value: 0.2 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Preparation of the Final Compounds:

EXAMPLE 14-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline

A solution of 3.9 g of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(diethoxy-phosphoryl)-acetylamino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazolinein 20 ml of tetrahydrofuran is added to a solution of 300 mg of lithiumchloride in 20 ml of water at ambient temperature. Then 2.35 g ofpotassium hydroxide flakes are added and the reaction mixture is cooledto −3° C. in an ice/acetone cooling bath. The solution of thehomomorpholin-4-yl-acetaldehyde hydrochloride obtained in Example II isthen added dropwise within 5 min at a temperature of 0° C. After theaddition has ended the reaction mixture is stirred for another 10 min at0° C. and for a further hour at ambient temperature. For working up 100ml of ethyl acetate are added and the aqueous phase is separated off.The organic phase is washed with saturated sodium chloride solution,dried over magnesium sulphate and evaporated down. The crude product ispurified by chromatography over a silica gel column using ethylacetate/methanol/conc. methanolic ammonia as eluant. The productobtained is stirred with a little diisopropyl ether, suction filteredand dried.

Yield: 2.40 g of (63% of theory)

R_(f) value: 0.09 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=542, 544 [M+H]⁺

The following compounds may also be prepared analogously to theforegoing Examples and other methods known from the literature: ExampleNo. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

EXAMPLE 2

Coated Tablets Containing 75 mg of Active Substance

1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mghydroxypropylmethylcellulose 15.0 mg magnesium stearate  1.5 mg 230.0mg Preparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks 13 mm in diameter areproduced in a tablet-making machine and these are then rubbed through ascreen with a mesh size of 1.5 mm using a suitable machine and mixedwith the rest of the magnesium stearate. This granulate is compressed ina tablet-making machine to form tablets of the desired shape.

-   -   Weight of core: 230 mg    -   die: 9 mm, convex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax.

-   -   Weight of coated tablet: 245 mg.

EXAMPLE 3

Tablets Containing 100 mg of Active Substance

Composition:

1 tablet contains: active substance 100.0 mg lactose  80.0 mg cornstarch  34.0 mg polyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg220.0 mgMethod of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

EXAMPLE 4

Tablets Containing 150 mg of Active Substance

Composition:

1 tablet contains: active substance 150.0 mg  powdered lactose 89.0 mgcorn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0mg magnesium stearate  1.0 mg 300.0 mg Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

EXAMPLE 5

Hard Gelatine Capsules Containing 150 mg of Active Substance

1 capsule contains: active substance 150.0 mg corn starch (dried)approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate3.0 mg approx. 420.0 mgPreparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

EXAMPLE 6

Suppositories Containing 150 mg of Active Substance

1 suppository contains: active substance 150.0 mg polyethyleneglycol1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitanmonostearate 840.0 mg 2,000.0 mg Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

EXAMPLE 7

Suspension Containing 50 mg of Active Substance

100 ml of suspension contain: active substance 1.00 gcarboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 gpropyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70%sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 mlPreparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

-   -   5 ml of suspension contain 50 mg of active substance.

EXAMPLE 8

Ampoules Containing 10 mg Active Substance

Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s.double-distilled water ad 2.0 mlPreparation:

The active substance is dissolved in the requisite amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

EXAMPLE 9

Ampoules Containing 50 mg of Active Substance

Composition: active substance 50.0 mg 0.01 N hydrochloric acid q.s.double-distilled water ad 10.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

EXAMPLE 10

Capsules for Powder Inhalation Containing 5 mg of Active Substance

1 capsule contains: active substance  5.0 mg lactose for inhalation 15.0mg 20.0 mgPreparation:

The active substance is mixed with lactose for inhalation. The mixtureis packed into capsules in a capsule-making machine (weight of the emptycapsule approx. 50 mg). weight of capsule: 70.0 mg size of capsule 3

EXAMPLE 11

Solution for Inhalation for Hand-Held Nebulisers Containing 2.5 mgActive Substance

1 spray contains: active substance 2.500 mg benzalkonium chloride 0.001mg 1N hydrochloric acid q.s. ad 15.000 mg ethanol/water (50/50)Preparation:

The active substance and benzalkonium chloride are dissolved inethanol/water (50/50). The pH of the solution is adjusted with 1 Nhydrochloric acid. The resulting solution is filtered and transferredinto suitable containers for use in hand-held nebulisers (cartridges).

Contents of the container: 4.5 g

1. A bicyclic heterocycle of formula

wherein R^(a) denotes a hydrogen atom or a C₁₋₄-alkyl group, R^(b)denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenylnucleus in each case is substituted by the groups R¹ to R³, while R¹ andR², which may be identical or different, in each case denote a hydrogen,fluorine, chlorine, bromine or iodine atom, a C₁₋₄-alkyl, hydroxy,C₁₋₄-alkoxy, C₂₋₃-alkenyl or C₂₋₃-alkynyl group, an aryl, aryloxy,arylmethyl or arylmethoxy group, a heteroaryl, heteroaryloxy,heteroarylmethyl or heteroarylmethoxy group, a methyl or methoxy groupsubstituted by 1 to 3 fluorine atoms or cyano, nitro or amino group, andR³ denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl ortrifluoromethyl group, R^(c) denotes a hydrogen atom or a fluorine,chlorine or bromine atom, a hydroxy or C₁₋₄-alkyloxy group, a methoxygroup substituted by 1 to 3 fluorine atoms, an ethyloxy groupsubstituted by 1 to 5 fluorine atoms, a C₂₋₄-alkyloxy group which issubstituted by a group R⁴, while R⁴ denotes a hydroxy, C₁₋₃-alkyloxy,C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,bis-(2-C₁₋₃-alkyloxy-ethyl)-amino, bis-(3-C₁₋₃-alkyloxy-propyl)-amino,pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl,homomorpholin-4-yl, piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl,homopiperazin-1-yl or 4-(C₁₋₃-alkyl)-homopiperazin-1-yl group, aC₃₋₇-cycloalkyloxy or C₃₋₇-cycloalkyl-C₁₋₄-alkyloxy group, atetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy ortetrahydropyran-4-yloxy group, a tetrahydrofuranyl-C₁₋₄-alkyloxy ortetrahydropyranyl-C₁₋₄-alkyloxy group, a pyrrolidin-3-yloxy,piperidin-3-yloxy or piperidin-4-yloxy group, a1-(C₁₋₃-alkyl)-pyrrolidin-3-yloxy, 1-(C₁₋₃-alkyl)-piperidin-3-yloxy or1-(C₁₋₃-alkyl)piperidin-4-yloxy group, a C₁₋₄-alkoxy group which issubstituted by a pyrrolidinyl, piperidinyl or homopiperidinyl groupsubstituted in the 1 position by the group R⁵, where R⁵ denotes ahydrogen atom or a C₁₋₃-alkyl group, or a C₁₋₄-alkoxy group which issubstituted by a morpholinyl or homomorpholinyl group substituted in the4 position by the group R⁵, where R⁵ is as hereinbefore defined, R^(e)and R^(d), which may be identical or different, in each case denote ahydrogen atom or a C₁₋₃-alkyl group and X denotes a methyne groupsubstituted by a cyano group or a nitrogen atom, while by the arylgroups mentioned in the definition of the above groups is meant in eachcase a phenyl group which is mono- or disubstituted by R⁶, while thesubstituents may be identical or different and R⁶ denotes a hydrogenatom, a fluorine, chlorine, bromine or iodine atom or a C₁₋₃-alkyl,hydroxy, C₁₋₃-alkyloxy, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy or cyano group, by the heteroarylgroups mentioned in the definition of the above groups is meant apyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, while theabove-mentioned heteroaryl groups are mono- or disubstituted in eachcase by the group R⁶, while the substituents may be identical ordifferent and R⁶ is as hereinbefore defined, and unless otherwisestated, the above-mentioned alkyl groups may be straight-chain orbranched, a tautomer or a stereoisomer thereof, or a mixture of suchthereof, or a salt thereof.
 2. The bicyclic heterocycle of formula Iaccording to claim 1, wherein R^(a) denotes a hydrogen atom, R^(b)denotes a phenyl group substituted by the groups R¹ to R³, while R¹denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl,trifluoromethyl or ethynyl group, a phenyloxy or phenylmethoxy group,while the phenyl moiety of the above-mentioned groups is optionallysubstituted by a fluorine or chlorine atom, or a pyridinyloxy orpyridinylmethoxy group, while the pyridinyl moiety of theabove-mentioned groups is optionally substituted by a methyl ortrifluoromethyl group, R² denotes a hydrogen, fluorine or chlorine atomand R³ denotes a hydrogen atom, R^(c) denotes a hydrogen atom, aC₁₋₃-alkyloxy group, a C₄₋₆-cycloalkyloxy orC₃₋₆-cycloalkyl-C₁₋₂-alkyloxy group, a tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,tetrahydrofuranyl-C₁₋₂-alkyloxy or tetrahydropyranyl-C₁₋₂-alkyloxygroup, an ethyloxy group which is substituted in the 2 position by agroup R⁴, where R⁴ denotes a hydroxy, C₁₋₃-alkyloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, bis-(2-methoxyethyl)-amino,pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl,homomorpholin-4-yl, piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl,homopiperazin-1-yl or 4-(C₁₋₃-alkyl)-homopiperazin-1-yl group, apropyloxy group which is substituted by a group R⁴ in the 3 position,while R⁴ is as hereinbefore defined, or a butyloxy group which issubstituted by a group R⁴ in the 4 position, while R⁴ is as hereinbeforedefined, R^(e) and R^(d), which may be identical or different, in eachcase denote a hydrogen atom or a methyl group and X denotes a nitrogenatom, while, unless otherwise stated, the above-mentioned alkyl groupsmay be straight-chain or branched, a tautomer or a stereoisomer thereof,or a mixture of such thereof, or a salt thereof.
 3. The bicyclicheterocycle of formula I according to claim 1, wherein R^(a) denotes ahydrogen atom, R^(b) denotes a 3-ethynylphenyl, 3-bromophenyl,3,4-difluorophenyl or 3-chloro-4-fluoro-phenyl group, R^(c) denotes ahydrogen atom, a methoxy, ethyloxy, 2-(methoxy)ethyloxy,3-(morpholin-4-yl)propyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cyclopropylmethoxy, cyclopentylmethoxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, tetrahydrofuran-2-yl methoxy,tetrahydrofuran-3-yl methoxy or tetrahydropyran-4-ylmethoxy group, R^(e)and R^(d) in each case denote a hydrogen atom and X denotes a nitrogenatom, a tautomer or a stereoisomer thereof, a mixture of such thereof,or a salt thereof.
 4. The bicyclic heterocycle of formula I according toclaim 1, wherein R^(a) denotes a hydrogen atom, R^(b) denotes a3-chloro-4-fluoro-phenyl group, R^(c) denotes a tetrahydrofuran-3-yloxygroup, R^(e) and R^(d) in each case denote a hydrogen atom and X denotesa nitrogen atom, a tautomer or a stereoisomer thereof, or a mixture ofsuch thereof or a salt thereof.
 5. The following compound of formula Iaccording to claim 1:4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazolineor a salt thereof.
 6. The physiologically acceptable salt of a compoundaccording to claim 1 with an inorganic or organic acid, or a mixturethereof, or a base.
 7. A pharmaceutical composition comprising acompound according to claim 1 or a physiologically acceptable saltthereof and one or more inert carriers and/or diluents.
 8. A method fortreating in a warm-blooded animal which comprises administering to saidanimal a therapeutically effective amount of a compound according toclaim
 1. 9. A method for preventing or treating diseases of the airwaysand lungs in a warm-blooded animal which comprises administering to saidanimal a therapeutically effective amount of a compound according toclaim
 1. 10. A method for treating diseases of the gastrointestinaltract or bile duct or gall bladder in a warm-blooded animal whichcomprises administering to said animal a therapeutically effectiveamount of a compound according to claim 1.